Regulation of neural differentiation by the transcription factor HES and the receptor Notch in mammals

哺乳动物中转录因子 HES 和受体 Notch 对神经分化的调节

• 批准号: 13670011
• 负责人: ISHIBASHI Makoto
• 金额: $ 2.62万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670011/
• 关键词: Neural differentiation; transcriptions factor; HES; Notch signaling; Notch

Helix-loop-helix type transcription factor, HES, inhibits neural differentiation in mice. HES has to be properly regulated as neural differentiation proceeds. Genetic analysis in Drosophila suggested that expression of Hes gene is under control of Notch signaling. To elucidate molecular mechanisms of this regulation, we examined the regulatory elements of Hes gene. The data showed that Hes expression is upregulated by Notch signaling through RBP-Jk/Su(H) binding sites.Although Notch signaling itself had been known to repress neural differentiation, it remained to be an open question whether Hes gene is downstream to Notch signaling. To demonstrate this cascade in mouse neural differentiation, neural precursor cells and the retina from Hes1/5 knockout embryos were infected with Notch-transducing retrovirus. While neural differentiation was inhibited by a Notch signal in wild type, Hes1 knockouts and Hes5 knockouts, neural precursors of Hes1 and Hes5 compound mutants normally differentiated in presence of a Notch signal. The data suggest that Hes1 and Hes5 are necessary for inhibition of neural differentiation by Notch, and that Hes1 and Hes5 are functionally redundant.

螺旋-环-螺旋型转录因子 HES 抑制小鼠神经分化。随着神经分化的进行，HES 必须得到适当的调节。果蝇的遗传分析表明 Hes 基因的表达受到 Notch 信号传导的控制。为了阐明这种调节的分子机制，我们检查了 Hes 基因的调节元件。数据显示，Notch 信号通过 RBP-Jk/Su(H) 结合位点上调 Hes 表达。尽管已知 Notch 信号本身可抑制神经分化，但 Hes 基因是否位于 Notch 信号下游仍然是一个悬而未决的问题。为了证明小鼠神经分化中的这种级联反应，Hes1/5 敲除胚胎的神经前体细胞和视网膜被 Notch 转导逆转录病毒感染。虽然野生型、Hes1 敲除型和 Hes5 敲除型中的神经分化受到 Notch 信号的抑制，但 Hes1 和 Hes5 复合突变体的神经前体通常在 Notch 信号存在下分化。数据表明Hes1和Hes5对于Notch抑制神经分化是必需的，并且Hes1和Hes5在功能上是冗余的。